From the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago (M.H.); Vall d'Hebron Institute of Oncology and Vall d'Hebron University Hospital, Barcelona (J.M.), the Spanish National Cancer Research Center, Madrid (D.O.), and Instituto de Investigación Biomédica de Málaga, Málaga (D.O.) - all in Spain; Institut Gustave Roussy, University of Paris Saclay, Villejuif (K.F.), the Department of Medical Oncology, Centre Hospitalier Universitaire Besançon, Besançon (A.T.-V.), and the Department of Medical Oncology, Institut Bergonié, Bordeaux (G.R.) - all in France; Centre Hospitalier de l'Université de Montréal-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal (F.S.), and BC Cancer Agency, Vancouver (K.N.C.) - both in Canada; Carolina Urologic Research Center, Myrtle Beach, SC (N.S.); Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (S.S.); Tulane University School of Medicine, New Orleans (O.S.); Huntsman Cancer Institute, University of Utah, Salt Lake City (N.A.); John Wayne Cancer Institute, Santa Monica, CA (P.T.); Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, Istanbul, Turkey (M.O.); AstraZeneca, Global Medicines Development, Oncology, Gaithersburg, MD (J.K.); Merck, Kenilworth, NJ (J.B.); and Global Medicines Development, Oncology (C.G.), Precision Medicine and Biosamples, R&D Oncology (C.C.), and Translational Medicine (C.A.A.), AstraZeneca, Cambridge, and the Institute of Cancer Research and Royal Marsden, London (J.B.) - both in the United Kingdom.
N Engl J Med. 2020 Dec 10;383(24):2345-2357. doi: 10.1056/NEJMoa2022485. Epub 2020 Sep 20.
We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported.
In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in , , or , and cohort B included 142 patients with at least one alteration in any of the other 12 prespecified genes. Crossover to olaparib was allowed after imaging-based disease progression for patients who met certain criteria. Overall survival in cohort A, a key secondary end point, was analyzed with the use of an alpha-controlled, stratified log-rank test at a data maturity of approximately 60%. The primary and other key secondary end points were reported previously.
The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population.
Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in , , or and whose disease had progressed during previous treatment with a next-generation hormonal agent, those who were initially assigned to receive olaparib had a significantly longer duration of overall survival than those who were assigned to receive enzalutamide or abiraterone plus prednisone as the control therapy, despite substantial crossover from control therapy to olaparib. (Funded by AstraZeneca and Merck Sharp and Dohme; PROfound ClinicalTrials.gov number, NCT02987543.).
我们之前报道过，在先前接受过下一代激素治疗后疾病进展的、同源重组修复基因有合格改变且患有转移性去势抵抗性前列腺癌的男性中，与医生选择的恩扎鲁胺或阿比特龙相比，奥拉帕利可显著延长影像学无进展生存期。总生存期的最终分析结果尚未报告。
在一项开放标签、3 期试验中，我们以 2:1 的比例随机分配患者接受奥拉帕利（256 例）或医生选择的恩扎鲁胺或阿比特龙加泼尼松作为对照治疗（131 例）。队列 A 包括至少有一个 、 或 改变的 245 例患者，队列 B 包括至少有一个其他 12 个预先指定基因中的任何一个改变的 142 例患者。对于符合某些标准的影像学疾病进展后的患者，允许交叉使用奥拉帕利。队列 A 的总生存期是关键次要终点，在数据成熟度约为 60%时，使用经过 alpha 控制的分层对数秩检验进行分析。主要和其他关键次要终点之前已经报道过。
队列 A 中奥拉帕利组的中位总生存期为 19.1 个月，对照组为 14.7 个月（死亡风险比，0.69；95%置信区间[CI]，0.50 至 0.97；P=0.02）。在队列 B 中，奥拉帕利组的中位总生存期为 14.1 个月，对照组为 11.5 个月。在总人群（队列 A 和 B）中，相应的生存期分别为 17.3 个月和 14.0 个月。总体而言，对照组的 131 例患者中有 86 例（66%）交叉接受了奥拉帕利治疗（83 例患者中的 56 例[67%]在队列 A 中）。一项调整交叉至奥拉帕利的敏感性分析显示，队列 A 的死亡风险比为 0.42（95%CI，0.19 至 0.91），队列 B 为 0.83（95%CI，0.11 至 5.98），总人群为 0.55（95%CI，0.29 至 1.06）。
在先前接受过下一代激素治疗后疾病进展且肿瘤至少有一个 、 或 改变的转移性去势抵抗性前列腺癌男性中，与接受恩扎鲁胺或阿比特龙加泼尼松作为对照治疗的患者相比，最初接受奥拉帕利治疗的患者总生存期显著延长，尽管从对照治疗交叉至奥拉帕利的患者比例很大。（由阿斯利康和默克 Sharp & Dohme 资助；PROfound 临床试验.gov 编号，NCT02987543）。
